Results of a Feasibility Study of Helpers Stay Quit Training for Smoking Relapse Prevention.

INTRODUCTION: Most smoking quit attempts end in relapse, and interventions focused on relapse prevention are lacking. Helpers Stay Quit (HSQ) is a novel behavioral relapse prevention intervention that teaches newly abstinent smokers to offer a "helping conversation" (HC) to help others quit tobacco. METHODS: Pre-post intervention feasibility study with state quitline participants ≥14 days abstinent. Measures at baseline, 3 months, and 6 months included smoking status, offering HCs, and cessation self-efficacy. Primary outcomes: self-reported 7-day point prevalence abstinence; offering HCs. Cox models explored association of HCs with relapse. Preliminary effects analysis using propensity score matching compared 30-day abstinence of quitline clients with study sample at 7 months. RESULTS: Participants (N = 104) were as follows: mean age of 53 years (SD 13.9 years), 48.1% male, mean of cigarettes smoked/day of 16.2 (SD 9.7). Compared with participants who remained abstinent (n = 82), relapsers (n = 22) had fewer HCs over 6 months (2.6 vs 7.2; 95% confidence interval [CI]: 1.4, 7.8, p = .006). Using adjusted Cox regression, the hazard ratio of relapse for each HC was 0.85 (95% CI: 0.74, 0.99, p = .03). Compared with a matched sample of quitline clients not exposed to HSQ, study participants were 49% more likely to report 30-day abstinence at 7-month quitline follow-up (95% CI: 40%, 59%, p < .0001). CONCLUSIONS: HSQ, delivered to newly abstinent smokers who received standard quitline treatment, was associated with less self-reported relapse. These promising preliminary study results warrant further research to evaluate HSQ as a novel behavioral intervention to prevent smoking relapse. IMPLICATIONS: To date, behavioral interventions for smoking relapse prevention that teach abstainers cessation skills to apply to themselves have not shown effectiveness. This feasibility study examines the preliminary efficacy of a conceptually novel, "help others" behavioral intervention approach for relapse prevention in newly abstinent smokers recruited from a state quitline. HSQ teaches the newly abstinent smoker communication and listening skills to encourage other smokers in their personal social network to quit. Exploratory analysis using propensity score matching suggests that participants exposed to HSQ were significantly more likely to self-report 30-day abstinence at quitline 7-month follow-up than other quitline clients.

Structure-based amelioration of PXR transactivation in a novel series of macrocyclic allosteric inhibitors of HIV-1 integrase.

Previous studies have identified a series of imidazo[1,2-a]pyridine (IZP) derivatives as potent allosteric inhibitors of HIV-1 integrase (ALLINIs) and virus infection in cell culture. However, IZPs were also found to be relatively potent activators of the pregnane-X receptor (PXR), raising the specter of induction of CYP-mediated drug disposition pathways. In an attempt to modify PXR activity without affecting anti-HIV-1 activity, rational structure-based design and modeling approaches were used. An X-ray cocrystal structure of (S,S)-1 in the PXR ligand binding domain (LBD) allowed an examination of the potential of rational structural modifications designed to abrogate PXR. The introduction of bulky basic amines at the C-8 position provided macrocyclic IZP derivatives that displayed potent HIV-1 inhibitory activity in cell culture with no detectable PXR transactivation at the highest concentration tested.

The discovery and preclinical evaluation of BMS-707035, a potent HIV-1 integrase strand transfer inhibitor.

BMS-707035 is an HIV-1 integrase strand transfer inhibitor (INSTI) discovered by systematic optimization of N-methylpyrimidinone carboxamides guided by structure-activity relationships (SARs) and the single crystal X-ray structure of compound 10. It was rationalized that the unexpectedly advantageous profiles of N-methylpyrimidinone carboxamides with a saturated C2-substitutent may be due, in part, to the geometric relationship between the C2-substituent and the pyrimidinone core. The single crystal X-ray structure of 10 provided support for this reasoning and guided the design of a spirocyclic series 12 which led to discovery of the morpholino-fused pyrimidinone series 13. Several carboxamides derived from this bicyclic scaffold displayed improved antiviral activity and pharmacokinetic profiles when compared with corresponding spirocyclic analogs. Based on the excellent antiviral activity, preclinical profiles and acceptable in vitro and in vivo toxicity profiles, 13a (BMS-707035) was selected for advancement into phase I clinical trials.

The Disparities of Coronary Artery Bypass Grafting Surgery Outcomes by Insurance Status: A Retrospective Cohort Study, 2007-2014.

BACKGROUND: Coronary artery bypass grafting (CABG) surgery is the gold standard treatment for complex coronary artery disease. Social determinants of health, including primary payer status, are disproportionately associated with adverse outcomes following surgical operations. We sought to examine associations between insurance status, in particular having Medicaid public insurance, and postoperative outcomes following isolated CABG surgeries. METHODS: A retrospective review was performed using Florida, California, New York, Maryland, and Kentucky State Inpatient Databases (2007-2014) for isolated CABG patients ≥ 18 years. Multivariate regression for postsurgical inpatient mortality, postsurgical complications, 30- and 90-day readmission rates, total charges, and length of stay yielded adjusted odds ratios (ORs) reported for outcomes by insurance status. RESULTS: Among 312,018 individuals, patients with Medicaid insurance and those designated as Uninsured incurred increased adjusted ORs of postsurgical inpatient mortality (56 and 64%, respectively) compared to Private Insurance. Additionally, Medicaid had the highest adjusted OR for 30-day readmission (OR 1.52, 95% CI 1.45-1.59), 90-day readmission (OR 1.53, 95% CI 1.47-1.59), postsurgical complications (OR 1.10, 95% CI 1.07-1.14) including pulmonary and infectious complications, postoperative length of stay, and total hospital charges (2016 dollars). CONCLUSIONS: Medicaid insurance, compared to Private Insurance, is significantly associated with worse outcomes after isolated CABG. Our results demonstrate that Medicaid as a patient's primary insurance payer is an independent predictor of perioperative risks. Further research may help explain the reasons for the differences in payer groups.

Reconstruction of midface defects with the osteocutaneous radial forearm flap: Evaluation of long term outcomes including patient reported quality of life.

BACKGROUND: Maxillectomy defects significantly impair quality of life. Prosthetics can overcome some of these issues, but has limitations. The role of the osteocutaneous radial forearm free flap (OC-RFFF) has been established for reconstruction of smaller maxillectomy defects, but its role in larger defects is not well defined. We aim to evaluate outcomes after midface reconstruction utilizing the OC-RFFF. METHODS: Retrospective review of prospective database collected between 2005 and 2014 of midface reconstruction using OC-RFFF in a tertiary care centre. Donor site complications and acute and long-term recipient site complications were measured. Health related quality of life was assessed using the University of Washington Quality of Life (UW-QOL) Questionnaire. RESULTS: A total of 68 midface defects were reconstructed using the OC-RFFF. Acute recipient site complications included three flap failures (4%), and two additional microvascular revision cases for vascular compromise. Late recipient complications included fistula (n = 10, 14%), ectropion (n = 7, 10%), diplopia (n = 6, 9%) and exposed hardware (n = 5, 7%). Resection of cheek skin or orbital rim correlated with orbital complications. The incidence of fistula was not affected by defect size or prior radiation. There were two donor site infections and no instances of forearm fracture. Patients undergoing OC-RFFF repair had mean scores for UW-QOL outcomes higher than published rates of obturator quality of life. CONCLUSION: The OC-RFFF is suited to a variety of midface defects and can be combined with hardware to reconstruct the orbital floor. Recipient site complications are common, but donor site morbidity is low and outcomes, including HR-QOL, are acceptable.

Adjusting Local Molecular Environment for Giant Ambient Thermal Contraction.

A low-energy triggered switch that can generate mechanoresponse has great technological potential. A submolecular moiety, S-dibenzocyclooctadiene (DBCOD) that is composed of a flexible eight-membered ring connecting to a phenyl ring at each end, undergoes a conformational change from twist-boat to chair under a low-energy stimulus such as near infrared irradiation, resulting in thermal contraction of DBCOD-based polymer. Experimental evidence corroborated by theoretical calculations indicates that introducing molecular asymmetry can reduce crystallinity significantly and consequently facilitate the kinetics of the conformational change. It has been demonstrated that the negative thermal expansion (NTE) coefficient of a DBCOD-based polymer system can be adjusted in a range from -1140 to -2350 ppm K-1 . -2350 ppm K-1 is ≈10 times better than the value reported by the second best NTE system.

Effect of Endobronchial Coils vs Usual Care on Exercise Tolerance in Patients With Severe Emphysema: The RENEW Randomized Clinical Trial.

IMPORTANCE: Preliminary clinical trials have demonstrated that endobronchial coils compress emphysematous lung tissue and may improve lung function, exercise tolerance, and symptoms in patients with emphysema and severe lung hyperinflation. OBJECTIVE: To determine the effectiveness and safety of endobronchial coil treatment. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial conducted among 315 patients with emphysema and severe air trapping recruited from 21 North American and 5 European sites from December 2012 through November 2015. INTERVENTIONS: Participants were randomly assigned to continue usual care alone (guideline based, including pulmonary rehabilitation and bronchodilators; n = 157) vs usual care plus bilateral coil treatment (n = 158) involving 2 sequential procedures 4 months apart in which 10 to 14 coils were bronchoscopically placed in a single lobe of each lung. MAIN OUTCOMES AND MEASURES: The primary effectiveness outcome was difference in absolute change in 6-minute-walk distance between baseline and 12 months (minimal clinically important difference [MCID], 25 m). Secondary end points included the difference between groups in 6-minute walk distance responder rate, absolute change in quality of life using the St George's Respiratory Questionnaire (MCID, 4) and change in forced expiratory volume in the first second (FEV1; MCID, 10%). The primary safety analysis compared the proportion of participants experiencing at least 1 of 7 prespecified major complications. RESULTS: Among 315 participants (mean age, 64 years; 52% women), 90% completed the 12-month follow-up. Median change in 6-minute walk distance at 12 months was 10.3 m with coil treatment vs -7.6 m with usual care, with a between-group difference of 14.6 m (Hodges-Lehmann 97.5% CI, 0.4 m to ∞; 1-sided P = .02). Improvement of at least 25 m occurred in 40.0% of patients in the coil group vs 26.9% with usual care (odds ratio, 1.8 [97.5% CI, 1.1 to ∞]; unadjusted between-group difference, 11.8% [97.5% CI, 1.0% to ∞]; 1-sided P = .01). The between-group difference in median change in FEV1 was 7.0% (97.5% CI, 3.4% to ∞; 1-sided P < .001), and the between-group St George's Respiratory Questionnaire score improved -8.9 points (97.5% CI, -∞ to -6.3 points; 1-sided P < .001), each favoring the coil group. Major complications (including pneumonia requiring hospitalization and other potentially life-threatening or fatal events) occurred in 34.8% of coil participants vs 19.1% of usual care (P = .002). Other serious adverse events including pneumonia (20% coil vs 4.5% usual care) and pneumothorax (9.7% vs 0.6%, respectively) occurred more frequently in the coil group. CONCLUSIONS AND RELEVANCE: Among patients with emphysema and severe hyperinflation treated for 12 months, the use of endobronchial coils compared with usual care resulted in an improvement in median exercise tolerance that was modest and of uncertain clinical importance, with a higher likelihood of major complications. Further follow-up is needed to assess long-term effects on health outcomes. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01608490.

Nanocoax-based electrochemical sensor.

We have used a facile polymer imprint process to fabricate a three-dimensional electrochemical nanosensor, the sensitivity of which is two decades higher than that of planar controls. The device is composed of an array of vertically oriented nanoscale coaxial electrodes, with the coax cores and shields serving as integrated working and counter electrodes, respectively, each with a nanoscale separation gap (coax annulus width). Arrays of ~10(6) devices per square millimeter were prepared with different gaps, with smaller gaps yielding higher sensitivity. A coax-based sensor with a 100 nm gap was found to have sensitivity 90 times greater than that of a planar sensor control, which had conventional millimeter-scale electrode gap spacing. We suggest that this enhancement is due to the combination of rapid diffusion of molecules between the closely spaced electrodes and the large number of nanoscale electrochemical cells operating in parallel, both of which enhance current per unit surface area compared to planar or other nanostructured devices.

Pre-operative intravenous dexamethasone prevents auditory threshold shift in a guinea pig model of cochlear implantation.

AIM: To protect hearing during cochlear implantation with systemic administration of dexamethasone. METHODS: Seventeen normal-hearing guinea pigs were randomly allocated to receive an intravenous injection of either normal saline (control), low- (0.2 mg/kg) or high- (2 mg/kg) dose dexamethasone 60 min prior to cochlear implantation. Auditory brainstem response (ABR) threshold shifts (2-32 kHz) were estimated between pre- and 4-week-postoperative levels. RESULTS: ABR threshold shifts (8-32 kHz) observed in control and low-dose steroid groups were significantly reduced in the high-dose steroid group. CONCLUSIONS: A single, high-dose injection of intravenous dexamethasone protected hearing during cochlear implantation.

Ultrasound-guided caudal epidural steroid injection for successful treatment of radiculopathy during pregnancy.

Aim: The aim of this case report is to describe ultrasound guidance for caudal epidural steroid injection during pregnancy. Case report: A 29-year-old, 32-week parturient presented with severe back and leg pain with MRI demonstrating herniation of the L5-S1 level. The disabling pain was refractory to conservative therapy, and an ultrasound-guided caudal epidural steroid injection was performed. There was significant pain relief in the first week with an uneventful subsequent pregnancy. Following delivery, the patient had no further recurrence of her presenting symptoms. Conclusion: Severe radiculopathy may be encountered during pregnancy, complicated by a limited number of treatment options. Ultrasound guidance should be considered during performance of caudal epidural injections in feasible cases.

Multimethod Formative Research to Improve the Training and Delivery of Tobacco-cessation Interventions in Behavioral Health Settings.

INTRODUCTION: Despite progress in reducing tobacco use within the general population, high prevalence of tobacco use continues in individuals with mental health and substance use disorders ("clients"). Tobacco use persists as the leading cause of premature mortality in this population. While behavioral health providers have frequent contacts with this population, they lack training in tobacco cessation counseling. METHODS: We conducted multimethod formative data collection consisting of key informant interviews with providers, field observations at clinical sites, and structured group interviews with behavioral health providers, and, separately, clients. Activities were conducted at 4 behavioral health agencies with 9 behavioral health clinic sites in southern Arizona. Recurring phrases and level of repetition were quantified to identify themes. These themes were then used to adapt the method of training delivery and revise the curriculum content for providers at the participating sites. RESULTS: Results indicated that providers had "training fatigue" and low satisfaction with multiple, online trainings. Further, providers noted issues including time constraints, competing clinical priorities, and low access to tobacco-cessation materials. Clients demonstrated high self-awareness around the importance of quitting smoking and professed frustration at being unable to quit, despite multiple attempts. Finally, both providers and clients agreed that a personal, supportive approach to cessation counseling was preferred. CONCLUSIONS: Using results from this formative research to revise delivery and content of existing smoking-cessation training for behavioral health providers may address barriers to assisting clients with smoking cessation. Additional research to determine the efficacy of the adapted training is needed.

Assessment of the Reliability of the Fiberoptic Endoscopic Evaluation of Swallowing as an Outcome Measure in Patients Undergoing Revision Anterior Cervical Discectomy and Fusion.

BACKGROUND: Dysphagia is one of the most common complications of anterior cervical spine surgery, and there is a need to establish that the means of testing for it are reliable and valid. The objective of this study was to measure observer variability of the fiberoptic endoscopic evaluation of swallowing (FEES) test, specifically when used for evaluation of dysphagia in patients undergoing revisionary anterior cervical decompression and fusion (ACDF). METHODS: Images from patients undergoing revision ACDF at a single institution were collected from May 1, 2010, through July 1, 2014. Two senior certified speech pathologists independently evaluated the swallowing function of patients preoperatively and at 2 weeks postoperatively. Their numeric evaluations of the Rosenbeck Penetration-Aspiration Scale and the Swallowing Performance Scale during the FEES were then compared for interrater reliability. RESULTS: Positive agreement between raters was 94% for the preoperative Penetration-Aspiration Scale (prevalence-adjusted bias-adjusted κ, 0.77). The postoperative Penetration-Aspiration Scale showed reliability coefficients for κ, Kendall's W, and intraclass correlation coefficient (ICC) of 0.34 (fair agreement), 0.70 (extremely strong agreement), and 0.35 (poor agreement), respectively. The preoperative Swallowing Performance Scale showed strong agreement, with a Kendall's W coefficient of 0.68, and fair reliability, with an ICC of 0.40. The postoperative Swallowing Performance Scale indicated extremely strong agreement between raters, with a Kendall's W of 0.82, and good agreement, with an ICC of 0.53. CONCLUSIONS: The FEES test appears to be a reliable assessor of dysphagia in patients undergoing ACDF and may be a useful measure for exploring outcomes in this population.

5,6,7,8-Tetrahydro-1,6-naphthyridine Derivatives as Potent HIV-1-Integrase-Allosteric-Site Inhibitors.

A series of 5,6,7,8-tetrahydro-1,6-naphthyridine derivatives targeting the allosteric lens-epithelium-derived-growth-factor-p75 (LEDGF/p75)-binding site on HIV-1 integrase, an attractive target for antiviral chemotherapy, was prepared and screened for activity against HIV-1 infection in cell culture. Small molecules that bind within the LEDGF/p75-binding site promote aberrant multimerization of the integrase enzyme and are of significant interest as HIV-1-replication inhibitors. Structure-activity-relationship studies and rat pharmacokinetic studies of lead compounds are presented.

Voice and swallowing outcomes following reoperative anterior cervical discectomy and fusion with a 2-team surgical approach.

OBJECTIVE Dysphagia and vocal cord palsy (VCP) are common complications after anterior cervical discectomy and fusion (ACDF). The reported incidence rates for dysphagia and VCP are variable. When videolaryngostroboscopy (VLS) is performed to assess vocal cord function after ACDF procedures, the incidence of VCP is reported to be as high as 22%. The incidence of dysphagia ranges widely, with estimates up to 71%. However, to the authors' knowledge, there are no prospective studies that demonstrate the rates of VCP and dysphagia for reoperative ACDF. This study aimed to investigate the incidence of voice and swallowing disturbances before and after reoperative ACDF using a 2-team operative approach with comprehensive pre- and postoperative assessment of swallowing, direct vocal cord visualization, and clinical neurosurgical outcomes. METHODS A convenience sample of sequential patients who were identified as requiring reoperative ACDF by the senior spinal neurosurgeon at the University of Alabama at Birmingham were enrolled in a prospective, nonrandomized study during the period from May 2010 until July 2014. Sixty-seven patients undergoing revision ACDF were enrolled using a 2-team approach with neurosurgery and otolaryngology. Dysphagia was assessed both preoperatively and postoperatively using the MD Anderson Dysphagia Inventory (MDADI) and fiberoptic endoscopic evaluation of swallowing (FEES), whereas VCP was assessed using direct visualization with VLS. RESULTS Five patients (7.5%) developed a new postoperative temporary VCP after reoperative ACDF. All of these cases resolved by 2 months postoperatively. There were no new instances of permanent VCP. Twenty-five patients had a new swallowing disturbance detected on FEES compared with their baseline assessment, with most being mild and requiring no intervention. Nearly 60% of patients showed a decrease in their postoperative MDADI scores, particularly within the physical subset. CONCLUSIONS A 2-team approach to reoperative ACDF was safe and effective, with no new cases of VCP on postoperative VLS. Dysphagia rates as assessed through the MDADI scale and FEES were consistent with other published reports.

Lung Volume Reduction Coils as a Novel Bronchoscopic Treatment for Emphysema.

Chronic obstructive pulmonary disease remains a major cause of morbidity and mortality worldwide. Despite regular advances in pharmacology, there remains great potential for addressing structural deficiencies, especially in emphysema. The loss of alveolar attachments to small bronchial tubes results in diffuse loss of elastic recoil and airway collapse during exhalation. This appears physiologically as hyperinflation of lung volumes with flattened diaphragms and significantly elevated residual volumes (RV) on pulmonary function testing (predicted RV > 175%).

Shielded Coaxial Optrode Arrays for Neurophysiology.

Recent progress in the study of the brain has been greatly facilitated by the development of new tools capable of minimally-invasive, robust coupling to neuronal assemblies. Two prominent examples are the microelectrode array (MEA), which enables electrical signals from large numbers of neurons to be detected and spatiotemporally correlated, and optogenetics, which enables the electrical activity of cells to be controlled with light. In the former case, high spatial density is desirable but, as electrode arrays evolve toward higher density and thus smaller pitch, electrical crosstalk increases. In the latter, finer control over light input is desirable, to enable improved studies of neuroelectronic pathways emanating from specific cell stimulation. Here, we introduce a coaxial electrode architecture that is uniquely suited to address these issues, as it can simultaneously be utilized as an optical waveguide and a shielded electrode in dense arrays. Using optogenetically-transfected cells on a coaxial MEA, we demonstrate the utility of the architecture by recording cellular currents evoked from optical stimulation. We also show the capability for network recording by radiating an area of seven individually-addressed coaxial electrode regions with cultured cells covering a section of the extent.

Anti-inflammatory effects of novel barbituric acid derivatives in T lymphocytes.

We have used a high throughput small molecule screen, using a fission yeast-based assay, to identify novel phosphodiesterase 7 (PDE7) inhibitors. One of the most effective hit compounds was BC12, a barbituric acid-based molecule that exhibits unusually potent immunosuppressive and immunomodulatory actions on T lymphocyte function, including inhibition of T cell proliferation and IL-2 cytokine production. BC12 treatment confers a >95% inhibition of IL-2 secretion in phytohaemagglutinin (PHA) plus phorbol-12-myristate-13-acetate (PMA) stimulated Jurkat T cells. The effect of BC12 on IL-2 secretion is not due to decreased cell viability; rather, BC12 blocks up-regulation of IL-2 transcription in activated T cells. BC12 also inhibits IL-2 secretion in human peripheral T lymphocytes stimulated in response to CD3/CD28 co-ligation or the combination of PMA and ionomycin, as well as the proliferation of primary murine T cells stimulated with PMA and ionomycin. A BC12 analog that lacks PDE7 inhibitory activity (BC12-4) displays similar biological activity, suggesting that BC12 does not act via PDE7 inhibition. To investigate the mechanism of inhibition of IL-2 production by BC12, we performed microarray analyses using unstimulated and stimulated Jurkat T cells in the presence or absence of BC12 or BC12-4. Our studies show these compounds affect the transcriptional response to stimulation and act via one or more shared targets to produce both anti-inflammatory and pro-stress effects. These results demonstrate potent immunomodulatory activity for BC12 and BC12-4 in T lymphocytes and suggest a potential clinical use as an immunotherapeutic to treat T lymphocyte-mediated diseases.

A nanocoaxial-based electrochemical sensor for the detection of cholera toxin.

Sensitive, real-time detection of biomarkers is of critical importance for rapid and accurate diagnosis of disease for point of care (POC) technologies. Current methods do not allow for POC applications due to several limitations, including sophisticated instrumentation, high reagent consumption, limited multiplexing capability, and cost. Here, we report a nanocoaxial-based electrochemical sensor for the detection of bacterial toxins using an electrochemical enzyme-linked immunosorbent assay (ELISA) and differential pulse voltammetry (DPV) or square wave voltametry (SWV). The device architecture is composed of vertically-oriented, nanoscale coaxial electrodes in array format (~10(6) coaxes per square millimeter). The coax cores and outer shields serve as integrated working and counter electrodes, respectively, exhibiting a nanoscale separation gap corresponding to ~100 nm. Proof-of-concept was demonstrated for the detection of cholera toxin (CT). The linear dynamic range of detection was 10 ng/ml-1 µg/ml, and the limit of detection (LOD) was found to be 2 ng/ml. This level of sensitivity is comparable to the standard optical ELISA used widely in clinical applications, which exhibited a linear dynamic range of 10 ng/ml-1 µg/ml and a LOD of 1 ng/ml. In addition to matching the detection profile of the standard ELISA, the nanocoaxial array provides a simple electrochemical readout and a miniaturized platform with multiplexing capabilities for the simultaneous detection of multiple biomarkers, giving the nanocoax a desirable advantage over the standard method towards POC applications.